This renewal builds on our current TTURC theme, to identify familial, early childhood and lifetime biopsychosocial pathways that determine: lifetime patterns of smoking uptake, use and cessation and the associated patterns of dependence. To do this, over the past 4 years, we have: a) implemented a prospective, three generation family study to examine the lifetime pathways to nicotine dependence; b) developed and validated promising new lifetime tobacco use and dependence phenotypic assessments; c) assessed measures of comorbidity with lower screening thresholds to include sub-clinical pathology) such as alcohol, psychiatric disorder, and temperament; and d) collected blood and saliva specimens. Our TTURC's New England Family Study (NEFS) has :reated a strong culture of transdisciplinary (TD) collaboration. Along with this "intellectual capital" is a rich and growing data-base and specimen sample repository from our unique 3 generation cohort, and a thriving career development site for future scientists. We propose 3 new NEFS studies to: 1) conduct a two-generation family study of genetic/familial influences on lifetime patterns of tobacco use phenotypes and comorbid psychiatric disorders; 2) conduct an endophenotypic study of sib pairs discordant for these tobacco use phenotypes, involving fMRI with nicotine challenge; and 3) examine mediation and moderation of the influence of neighborhood factors ion the progression of tobacco use, alcohol and other drug use in adolescents. With five strong Cores and a select Igroup of new scientists with expertise in the new content areas of the three NEFS studies: neuroscience, brain imaging, behavioral genetics, the co-morbidity of psychiatric, alcohol and other conditions, social context, spatial correlation, as well as measures and methods development, this renewal capitalizes on untapped opportunities to expand the rich database already accumulating. This renewal, precisely because it builds directly on the current TTURC theme, creates considerably greater opportunities for TD collaboration. The consolidated 10-year research program, provides an economy of scale with enormous "value added" potential to maximize the investments already made, significantly break new ground, and ensure that the TD whole is greater than the sum of its parts.